2-amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to 2-amino-imidazo[4,5-d]pyridazin-4-ones and 2-amino-imidazo[4,5-c]pyridin-4-ones of general formula  
                 
 
wherein R 1  to R 4  and X are defined as in claims  1  to  6 , the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/102,048 filed Apr. 8, 2005, which claims the benefit under35 U.S.C. 119(a) of German Patent Applications 102 004 017 739 (filedApr. 10, 2004) and 102 004 025 552 (filed May 25, 2004), all of whichare hereby incorporated herein by reference in their entireties. Thisapplication also claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Patent Application 60/568,137 (filed May 5, 2004) and60/582,265 (filed Jun. 23, 2004), which are hereby incorporated byreference in their entireties.

The present invention relates to new substitutedimidazo[4,5-d]pyridazin-4-ones and 2-amino-imidazo[4,5-c]pyridin-4-onesof general formula I:

the tautomers, enantiomers, diastereomers, salts, particularlyphysiologically acceptable salts with inorganic or organic acids, andmixtures thereof, which have valuable pharmacological properties, suchas an inhibiting effect on the activity of the enzymedipeptidylpeptidase-IV (DPP-IV), the preparation thereof, the usethereof for preventing or treating illnesses or conditions connectedwith an increased DPP-IV activity or capable of being prevented oralleviated by reducing the DPP-IV activity, such as type I or type IIdiabetes mellitus, the pharmaceutical compositions containing a compoundof general formula (I) or a physiologically acceptable salt thereof, andprocesses for the preparation thereof.

Imidazo[4,5-d]pyridazin-4-ones and imidazo[4,5-c]pyridin-4-ones whichare substituted bicyclic groups in the 2 position are known from WO03/104229.

In the above formula I

R¹ denotes:

-   -   an arylmethyl or arylethyl group,    -   a heteroarylmethyl or heteroarylethyl group,    -   an arylcarbonylmethyl group,    -   a heteroarylcarbonylmethyl group, or    -   an arylprop-2-enyl or heteroarylprop-2-enyl group, wherein the        propenyl chain may be substituted by 1 to 4 fluorine atoms or a        cyano, C₁₋₃-alkyloxy-carbonyl or nitro group,

X denotes a nitrogen atom or a C—R⁵ group, while R⁵ denotes a hydrogenatom or a C₁₋₃-alkyl group,

R² denotes

-   -   a hydrogen atom,    -   a C₁₋₆-alkyl group,    -   an aryl or heteroaryl group,    -   a C₁₋₆-alkyl group substituted by a group R_(a), where        -   R_(a) denotes            -   a C₃₋₇-cycloalkyl group, wherein one or two methylene                groups may each be replaced independently of one another                by an oxygen or sulphur atom, by an —NH— or                —N(C₁₋₃-alkyl)- group, or by a carbonyl, sulphinyl or                sulphonyl group, or            -   a trifluoromethyl, aryl, heteroaryl, cyano, carboxy,                C₁₋₃-alkoxy-carbonyl, aminocarbonyl,                C₁₋₃-alkylamino-carbonyl,                di-(C₁₋₃-alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl,                piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,                piperazin-1-ylcarbonyl,                4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl,                heteroarylcarbonyl, C₁₋₃-alkylsulphinyl,                C₁₋₃-alkylsulphonyl, hydroxy, C₁₋₃-alkoxy,                C₁₋₃-alkylsulphanyl, amino, C₁₋₃-alkylamino,                di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,                morpholin-4-yl, piperazin-1-yl, or                4-(C₁₋₃-alkyl)-piperazin-1-yl group,    -   a trifluoromethyl, carboxy, C₁₋₄-alkoxy-carbonyl, aminocarbonyl,        C₁₋₃-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,        pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,        morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl,        4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,        C₁₋₄-alkoxy, C₁₋₄-alkylsulphanyl, amino, C₁₋₃-alkylamino or        di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,        morpholin-4-yl, piperazin-1-yl or 4-(C₁₋₃-alkyl)-piperazin-1-yl        group,    -   a C₃₋₇-cycloalkyl group wherein one or two methylene groups        independently of one another may each be replaced by an oxygen        or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)- group, or by a        carbonyl, sulphinyl or sulphonyl group, or a C₃₋₆-alkenyl or        C₃₋₆-alkynyl group,

R³ denotes

-   -   a C₅₋₇-cycloalkenylmethyl group optionally substituted by a        C₁₋₃-alkyl group,    -   an arylmethyl or heteroarylmethyl group,    -   a straight-chain or branched C₂₋₈-alkenyl group which may be        substituted by 1 to 15 fluorine atoms or a cyano, nitro or        C₁₋₃-alkoxy-carbonyl group,    -   or a straight-chain or branched C₃₋₈-alkynyl group which may be        substituted by 1 to 9 fluorine atoms or a cyano, nitro or        C₁₋₃-alkoxy-carbonyl group,        and

R⁴ denotes

-   -   an amino group substituted by the groups R¹⁵ and R¹⁶ wherein        -   R¹⁵ denotes            -   a hydrogen atom, a C₁₋₆-alkyl, C₃₋₆-cycloalkyl,                C₃₋₆-cycloalkyl-C₁₋₃-alkyl, aryl or aryl-C₁₋₃-alkyl                group and        -   R¹⁶ denotes            -   a R¹⁷—C₂₋₃-alkyl group, while the C₂₋₃-alkyl moiety is                straight-chain and may be substituted by 1 to 4                C₁₋₃-alkyl groups, which may be identical or different,                and the C₂₋₃-alkyl group may be linked to R¹⁷ from                position 2 onwards, and                -   R¹⁷ denotes an amino or C₁₋₃-alkylamino group,    -   an amino group substituted by the groups R¹⁵ and R¹⁸ wherein        -   R¹⁵ is as hereinbefore defined and R¹⁸ denotes a            C₃₋₁₀-cycloalkyl-C₁₋₂-alkyl- group substituted in the 1            position of the cycloalkyl group by R¹⁹ or a            C₃₋₁₀-cycloalkyl group substituted in 1 or 2 position by a            R¹⁹—C₁₋₂-alkyl-group, while R¹⁹ denotes an amino or            C₁₋₃-alkylamino group,    -   an amino group substituted by the groups R¹⁵ and R²⁰ wherein        -   R¹⁵ is as hereinbefore defined and R²⁰ denotes a C₄— or            C₈₋₁₀-cycloalkyl group wherein a methylene group is replaced            by an —NH— group from position 3 onwards of the C₄— or            C₈₋₁₀-cycloalkyl group, or    -   an amino group substituted by the groups R¹⁵ and R²¹ wherein        -   R¹⁵ is as hereinbefore defined and R²¹ denotes a C₃₋₄ or            C₈₋₁₀-cycloalkyl group substituted in the 2 or 3 position by            an amino or C₁₋₃-alkylamino group,            while the above-mentioned groups R¹⁸, R²⁰, and R²¹ may be            mono- or disubstituted by R_(b), the substituents may be            identical or different, and R_(b) denotes a fluorine atom, a            C₁₋₃-alkyl, trifluoromethyl, cyano, amino, C₁₋₃-alkylamino,            hydroxy or C₁₋₃-alkyloxy group, and wherein one or two            methylene groups of the cycloalkyl group independently of            one another may each be replaced by an oxygen or sulphur            atom or by an —NH— or —N(C₁₋₃-alkyl)- group, or by a            carbonyl, sulphinyl, or sulphonyl group.

By the aryl groups mentioned in the definition of the above groups ismeant phenyl or naphthyl groups, which may be mono-, di-, ortrisubstituted independently of one another by R_(h), while thesubstituents may be identical or different, and R_(h) denotes afluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyano,nitro, amino, aminocarbonyl, C₁₋₃-alkoxy-carbonyl, aminosulphonyl,methylsulphonyl, acetylamino, methylsulphonylamino, C₁₋₃-alkyl,cyclopropyl, ethenyl, ethynyl, morpholinyl, hydroxy, C₁₋₃-alkyloxy,difluoromethoxy, or trifluoromethoxy group, and additionally whereineach hydrogen atom may be replaced by a fluorine atom.

By the heteroaryl groups mentioned in the definition of theabove-mentioned groups is meant:

-   -   a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl, or isoquinolinyl group, or    -   a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or        two methyne groups are replaced by nitrogen atoms, or    -   an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or        isoquinolinyl group,    -   wherein one to three methyne groups are replaced by nitrogen        atoms, and the above-mentioned heteroaryl groups may be mono- or        disubstituted by R_(h), while the substituents may be identical        or different and R_(h) is as hereinbefore defined.

By the above-mentioned cycloalkyl groups, as defined, is meant bothmonocyclic and also polycyclic ring systems, while the polycyclic groupsmay be annelated, spiro-linked or bridged in structure, e.g., thepolycyclic groups may be decalin, octahydroindene, norbornane,spiro[4,4]nonane, spiro[4,5]decane, bicyclo[2,1,1]hexane,bicyclo[2,2,2]octane, bicyclo[3,2,1]octane, bicyclo[3,2,2]nonane,bicyclo[3,3,1]nonane, bicyclo[3,3,2]decane, or adamantine.

Unless otherwise stated, the above-mentioned alkyl, alkenyl, and alkynylgroups may be straight-chain or branched.

The tautomers, enantiomers, diastereomers, the mixtures thereof, theprodrugs thereof, and the salts thereof.

The carboxy groups mentioned in the definition of the abovementionedgroups may be replaced by a group which can be converted into a carboxygroup in vivo or by a group which is negatively charged underphysiological conditions,

Furthermore, the amino and imino groups mentioned in the definition ofthe abovementioned groups may be substituted by a group which can becleaved in vivo. Such groups are described for example in WO 98/46576and by N. M. Nielsen et al. in International Journal of Pharmaceutics39, 75-85 (1987).

By a group which can be converted in vivo into a carboxy group is meant,for example, a hydroxymethyl group, a carboxy group esterified with analcohol, wherein the alcohol moiety is preferably a C₁₋₆-alkanol, aphenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, while a C₅₋₈-cycloalkanol mayadditionally be substituted by one or two C₁₋₃-alkyl groups, aC₅₋₈-cycloalkanol, wherein a methylene group in the 3 or 4 position isreplaced by an oxygen atom or by an imino group optionally substitutedby a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxycarbonyl, orC₂₋₆-alkanoyl group, and the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol, orphenyl-C₃₋₅-alkynol, with the proviso that no bonds to the oxygen atomstart from a carbon atom that carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol with a total of 8 to 10carbon atoms that may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol, or an alcohol of formulaR_(p)—CO—O—(R_(q)CR_(r))—OH,wherein

-   -   R_(p) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, C₁₋₈-alkyloxy,        C₅₋₇-cycloalkyloxy, phenyl, or phenyl-C₁₋₃-alkyl group,    -   R_(q) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl, or        phenyl group and R_(r) denotes a hydrogen atom or a C₁₋₃-alkyl        group,

By a group which is negatively charged under physiological conditions ismeant, for example, a tetrazol-5-yl, phenylcarbonylaminocarbonyl,trifluoromethylcarbonylaminocarbonyl, C₁₋₆-alkylsulphonylamino,phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl, orperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group.

By a group which can be cleaved in vivo from an imino or amino group ismeant, for example, a hydroxy group, an acyl group such as aphenylcarbonyl group optionally mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups,while the substituents may be identical or different, a pyridinoyl groupor a C₁₋₁₆-alkanoyl group such as the formyl, acetyl, propionyl,butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl orallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxygroup, wherein hydrogen atoms may be wholly or partially replaced byfluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl,nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy,ethylcarbonyloxy, 2,2,2-trichloro-ethylcarbonyloxy, propylcarbonyloxy,isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy,pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy,decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy orhexadecylcarbonyloxy group, a phenyl-C₁₋₆-alkoxycarbonyl group such asthe benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonylgroup, a 3-amino-propionyl group wherein the amino group may be mono- ordisubstituted by C₁₋₆-alkyl or C₃₋₇-cycloalkyl groups and thesubstituents may be identical or different, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(p)—CO—O—(R_(q)CR_(r))—O—CO—, C₁₋₆-alkyl-CO—NH—(R_(s)CR_(t))—O—CO— orC₁₋₆-alkyl-CO—O—(R_(s)CR_(t))—(R_(s)CR_(t))—O—CO— group, wherein R_(p)to R_(r) are as hereinbefore defined, and R_(s) and R_(t), which may beidentical or different, denote hydrogen atoms or C₁₋₃-alkyl groups.

Moreover, unless otherwise stated, the saturated alkyl and alkoxymoieties containing more than 2 carbon atoms mentioned in thedefinitions above also include the branched isomers thereof such as theisopropyl, tert.butyl, isobutyl group, etc.

R¹ may denote for example a 2-cyanobenzyl, 3-fluorobenzyl,3-methoxybenzyl, 4-bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl,2-cyano-4-fluorobenzyl, 3,5-dimethoxybenzyl, 2,6-dicyanobenzyl,5-cyanofuranylmethyl, oxazolylmethyl, isoxazolylmethyl,5-methoxycarbonylthienylmethyl, pyridinylmethyl,3-cyanopyridin-2-ylmethyl, 6-cyanopyridin-2-ylmethyl,6-fluoropyridin-2-ylmethyl, 3-(2-cyanophenyl)-prop-2-enyl,3-(pyridin-2-yl)-prop-2-enyl, 3-(pentafluorophenyl)-prop-2-enyl,phenyl-carbonylmethyl, 3-methoxyphenylcarbonylmethyl, naphthyl-1-methyl,4-cyanonaphth-1-ylmethyl, quinolin-1-ylmethyl,4-cyanoquinolin-1-ylmethyl, isoquinolin-1-ylmethyl,4-cyanoisoquinolin-1-ylmethyl, 4-cyanoisoquinolin-3-ylmethyl,3-methylisoquinolin-1-ylmethyl, quinazolin-2-ylmethyl,4-methylquinazolin-2-ylmethyl, [1,5]naphthiridin-2-ylmethyl,[1,5]naphthiridin-3-ylmethyl, quinoxalin-6-ylmethyl, or2,3-dimethyl-quinoxalin-6-ylmethyl group.

R² may denote, for example, a hydrogen atom, a methyl, ethyl, propyl,2-propyl, butyl, 2-butyl, 2-methylpropyl, tert.-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-propen-1-yl, 2-propyn-1-yl,cyclopropylmethyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl,2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(dimethylamino)ethyl,pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl,carboxy, methoxycarbonyl, ethoxycarbonyl, carboxymethyl,(methoxycarbonyl)methyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl,morpholinocarbonyl, (aminocarbonyl)methyl, (methylaminocarbonyl)methyl,(dimethylaminocarbonyl)methyl, (pyrrolidinocarbonyl)methyl,(piperidinocarbonyl)methyl, (morpholinocarbonyl)methyl, cyanomethyl,2-cyanoethyl, or pyridinyl group.

R³ may denote for example a 2-propen-1-yl, 2-methyl-2-propen-1-yl,1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 3-methyl-3-buten-1-yl,1-cyclopenten-1-yl methyl, (2-methyl-1-cyclopenten-1-yl)methyl,1-cyclohexen-1-ylmethyl, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl,2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-cyanobenzyl,3-fluorobenzyl, 2-methoxy-benzyl, 2-furanylmethyl, 3-furanylmethyl,2-thienylmethyl, or 3-thienylmethyl group.

R⁴ may denote for example a (2-aminocyclopropyl)amino,N-(2-aminocyclopropyl)-N-methyl-amino, (2-aminocyclobutyl)amino,N-(2-aminocyclobutyl)-N-methyl-amino,N-(3-aminocyclobutyl)-N-methyl-amino, N-(2-aminoethyl)-N-methyl-amino,N-(1-aminoprop-2-yl)-N-methyl-amino, N-(2-aminopropyl)-N-methyl-amino,N-(1-amino-2-methyl-prop-2-yl)-N-methyl-amino,N-(2-amino-2-methyl-propyl)-N-methyl-amino,N-[(1-aminocyclopropyl)methyl]-N-methyl-amino, orN-(1-aminomethylcyclopropyl)-N-methyl-amino group.

Preferred compounds of general formula I are those wherein

-   -   R¹ and R⁴ are as hereinbefore defined,    -   X denotes a nitrogen atom or a —CH group,    -   R² denotes a hydrogen atom, a C₁₋₄-alkyl, C₃₋₆-cycloalkyl or        phenyl group and    -   R³ denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl,        cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl,        chlorobenzyl, bromobenzyl, iodobenzyl, methoxybenzyl or        cyanobenzyl group,        the enantiomers, the diastereomers, the mixtures thereof and the        salts thereof.

Particularly preferred compounds of general formula I are those wherein

-   -   R¹ denotes a phenylmethyl, phenylcarbonylmethyl,        phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl,        naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl,        quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or        benzotriazolylmethyl group which may be substituted in each case        by one or two fluorine, chlorine, bromine atoms or one or two        cyano, nitro, amino, C₁₋₃-alkyl, C₁₋₃-alkyloxy and morpholinyl        groups, while the substituents are identical or different,    -   X denotes a nitrogen atom or a —CH group,    -   R² denotes a hydrogen atom,    -   R³ denotes a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl,        cyclopent-1-enyl-methyl, furanylmethyl, thienylmethyl,        chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group and    -   R⁴ denotes an N-(2-aminoethyl)-N-methyl-amino group wherein the        ethyl group may be substituted by 1 to 4 methyl groups,        the tautomers, the mixtures thereof and the salts thereof.

Most particularly preferred are those compounds of general formula Iwherein

-   -   R¹ denotes a isoquinolinylmethyl, quinazolinylmethyl or benzyl        group which may be substituted by a methyl or cyano group,    -   X denotes a nitrogen atom or a —CH group,    -   R² denotes a hydrogen atom,    -   R³ denotes a 2-butyn-1-yl group and    -   R⁴ denotes an N-(2-aminoethyl)-N-methyl-amino,        N-(2-aminopropyl)-N-methyl-amino or        N-(2-amino-2-methylpropyl)-N-methyl-amino group,        the tautomers and the salts thereof.

The following preferred compounds may be mentioned by way of example:

-   (a)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (b)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (c)    (S)-2-[N-(2-aminopropyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenyl-methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (d)    2-[N-(2-amino-2-methylpropyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenyl-methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (e)    (S)-2-[N-(2-aminopropyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (f)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one-   (g)    (S)-2-[N-(2-aminopropyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-cyano-isoquinolin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one    and the tautomers and the salts thereof.

According to the invention the compounds of general formula I areobtained by methods known, per se, for example by the following methods:A) Reacting a Compound of General Formula II

wherein

-   -   R¹ to R³ and X are as hereinbefore defined and    -   Z¹ denotes a leaving group such as a halogen atom, a substituted        hydroxy, mercapto, sulphinyl, sulphonyl or sulphonyloxy group        such as a chlorine or bromine atom, a methanesulphonyl or        methanesulphonyloxy group, with R⁴—H or salts thereof, where R⁴        is as hereinbefore defined.

The reaction is expediently carried out in a solvent such asisopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide,dimethylsulphoxide, ethyleneglycolmonomethylether,ethyleneglycoldiethylether or sulpholane, optionally in the presence ofan inorganic or tertiary organic base, e.g. sodium carbonate, potassiumcarbonate or potassium hydroxide, a tertiary organic base, e.g.triethylamine, or in the presence of N-ethyl-diisopropylamine (Hünigbase), while these organic bases may simultaneously also serve assolvent, and optionally in the presence of a reaction accelerator suchas an alkali metal halide or a palladium-based catalyst at temperaturesbetween −20 and 180° C., but preferably at temperatures between −10 and120° C. The reaction may, however, also be carried out without a solventin an excess of ethylenediamine derivative with conventional heating orin the microwave oven.B) Deprotecting a Compound of General Formula III

wherein

-   -   R¹, R², R³ and X are as hereinbefore defined and    -   Z² denotes one of the groups mentioned hereinbefore for R⁴ which        contain an amino group not directly bound to the basic        imidazopyridazinone structure which is Boc-protected in Z²,        where Boc denotes a tert.-butyloxycarbonyl group.

The tert.-butyloxycarbonyl group is preferably cleaved by treating withan acid such as trifluoroacetic acid or hydrochloric acid or by treatingwith bromotrimethylsilane or iodotrimethylsilane, optionally using asolvent such as methylene chloride, ethyl acetate, dioxane, methanol,isopropanol or diethyl ether at temperatures between 0 and 80° C.

In the reactions described hereinbefore, any reactive groups presentsuch as amino, alkylamino or imino groups may be protected during thereaction by conventional protecting groups which are cleaved again afterthe reaction.

For example, protecting groups for an amino, alkylamino or imino groupmay be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g., in the presenceof iodotrimethylsilane, at temperatures between 0° C. and 120° C.,preferably at temperatures between 10° C. and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g., with hydrogen in the presence ofa catalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0° C. and 100° C., but preferably at ambient temperaturesbetween 20° C. and 60° C., and at a hydrogen pressure of 1 to 7 bar, butpreferably from 3 to 5 bar. However, a 2.4-dimethoxybenzyl group ispreferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert.-butyl or tert. butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50° C. and 120° C. or by treatingwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran, at temperatures between 0° C. and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20° C. and 50° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis-and trans-isomers, and compounds with at least one optically activecarbon atom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated bychromatography into their cis and trans isomers, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known, per se (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971), into their opticalenantiomers and compounds of general formula I with at least 2asymmetric carbon atoms may be resolved into their diastereomers on thebasis of their physical-chemical differences using methods known, perse, e.g., by chromatography and/or fractional crystallisation, and, ifthese compounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as, e.g., esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g., on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be, for example, (+)- or(−)-menthol and an optically active acyl group in amides, for example,may be a (+)- or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

Moreover, the new compounds of formula (I), if they contain a carboxygroup, may if desired be converted into the salts thereof with inorganicor organic bases, particularly for pharmaceutical use into thephysiologically acceptable salts thereof. Suitable bases for thisinclude, for example, sodium hydroxide, potassium hydroxide,cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulae II and III used as starting compoundsare either known from the literature or may be prepared by methods knownfrom the literature (see Examples I to XI).

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on the enzyme DPP-IV.

The biological properties of the new compounds were investigated asfollows:

The ability of the substances and their corresponding salts to inhibitthe DPP-IV activity can be demonstrated in an experiment in which anextract of the human colon carcinoma cell line Caco-2 is used as the DPPIV source. The differentiation of the cells in order to induce theDPP-IV expression was carried out in accordance with the description byReiher et al. in an article entitled “Increased expression of intestinalcell line Caco-2”, which appeared in Proc. Natl. Acad. Sci. Vol. 90, pp.5757-5761 (1993).

The cell extract was obtained from cells solubilised in a buffer (10 mMTris HCl, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0)by centrifugation at 35,000 g for 30 minutes at 4° C. (to remove celldebris).

The DPP-IV assay was carried out as follows:

50 μl of substrate solution (AFC; AFC isamido-4-trifluoromethylcoumarin), final concentration 100 μM, wereplaced in black microtitre plates. 20 μl of assay buffer (finalconcentrations 50 mM Tris HCl, pH 7.8, 50 mM NaCl, 1% DMSO) was pipettedin. The reaction was started by the addition of 30 μl of solubilisedCaco-2 protein (final concentration 0.14 μg of protein per well). Thetest substances under investigation were typically added prediluted to20 μl, while the volume of assay buffer was then reduced accordingly.The reaction was carried out at ambient temperature, the incubationperiod was 60 minutes. Then the fluorescence was measured in a Victor1420 Multilabel Counter, with the excitation wavelength at 405 nm andthe emission wavelength at 535 nm. Dummy values (corresponding to 0%activity) were obtained in mixtures with no Caco-2 protein (volumereplaced by assay buffer), control values (corresponding to 100%activity) were obtained in mixtures without any added substance. Thepotencies of the test substances in question, expressed as IC₅₀ values,were calculated from dosage/activity curves consisting of 11 measuredpoints in each case. The following results were obtained: Compound DPPIV inhibition (Example No.) IC₅₀ [nM] 1 1 1(1) 10 1(2) 34 2 76 2(1) 3363 2

The compounds prepared according to the invention are well tolerated asno toxic side effects after the oral administration of 10 mg/kg of thecompound of Example 1, for example.

In view of their ability to inhibit DPP-IV activity, the compounds ofgeneral formula I according to the invention, and the correspondingpharmaceutically acceptable salts thereof, are suitable for influencingany conditions or diseases that can be affected by the inhibition of theDPP-IV activity. It is therefore to be expected that the compoundsaccording to the invention will be suitable for the prevention ortreatment of diseases or conditions such as type I and type II diabetesmellitus, diabetic complications (e.g., retinopathy, nephropathy orneuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia,insulin resistance, metabolic syndrome, dyslipidaemias of variousorigins, arthritis, atherosclerosis and related diseases, obesity,allograft transplantation and osteoporosis caused by calcitonin. Inaddition, these substances are suitable for preventing B-celldegeneration such as, e.g., apoptosis or necrosis of pancreatic B-cells.The substances are also suitable for improving or restoring the functionof pancreatic cells and additionally increasing the size and number ofpancreatic B-cells. Additionally, on the basis of the role of theglucagon-like peptides such as e.g. GLP-1 and GLP-2 and their link withDPP-IV inhibition, it is expected that the compounds according to theinvention will be suitable for achieving, inter alia, a sedative ortranquillising effect, as well as having a favourable effect oncatabolic states after operations or hormonal stress responses orpossibly reducing mortality and morbidity after myocardial infarct.Moreover, they are suitable for treating any conditions connected withthe effects mentioned above and mediated by GLP-1 or GLP-2. Thecompounds according to the invention may also be used as diuretics orantihypertensives and are suitable for preventing and treating acutekidney failure. The compounds according to the invention may also beused to treat inflammatory complaints of the respiratory tract. They arealso suitable for preventing and treating chronic inflammatory boweldiseases such as e.g. irritable bowel syndrome (IBS), Crohn's disease orulcerative colitis and also pancreatitis. It is also expected that theycan be used for all kinds of injury or damage to the gastrointestinaltract such as may occur in colitis and enteritis, for example. Moreover,it is expected that DPP-IV inhibitors and hence the compounds accordingto the invention can be used to treat infertility or to improvefertility in humans or mammals, particularly if the infertility isconnected with insulin resistance or with polycystic ovary syndrome. Onthe other hand these substances are suitable for influencing spermmotility and are thus suitable for use as male contraceptives. Inaddition, the substances are suitable for treating growth hormonedeficiencies connected with restricted growth, and may reasonably beused for all indications for which growth hormone may be used. Thecompounds according to the invention are also suitable, on the basis oftheir inhibitory effect on DPP-IV, for treating various autoimmunediseases such as e.g. rheumatoid arthritis, multiple sclerosis,thyroiditis and Basedow's disease, etc. They may also be used to treatviral diseases and also, for example, in HIV infections, for stimulatingblood production, in benign prostatic hyperplasia, gingivitis, as wellas for the treatment of neuronal defects and neurodegenerative diseasessuch as Alzheimer's disease, for example. The compounds described mayalso be used for the treatment of tumours, particularly for modifyingtumour invasion and also metastasisation; examples here are their use intreating T-cell lymphomas, acute lymphoblastic leukaemia, cell-basedthyroid carcinomas, basal cell carcinomas or breast cancers. Otherindications are stroke, ischaemia of various origins, Parkinson'sdisease and migraine. In addition, further indications includefollicular and epidermal hyperkeratoses, increased keratinocyteproliferation, psoriasis, encephalomyelitis, glomerulonephritis,lipodystrophies, as well as psychosomatic, depressive andneuropsychiatric diseases of all kinds.

The compounds according to the invention may also be used in conjunctionwith other active substances. Suitable therapeutic agents for suchcombinations include for example antidiabetic agents such as metformin,sulphonylureas (e.g., glibenclamide, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidinediones (e.g., rosiglitazone,pioglitazone), PPAR-gamma agonists (e.g., GI 262570) and antagonists,PPAR-gamma/alpha modulators (e.g., KRP 297), alpha-glucosidaseinhibitors (e.g., acarbose, voglibose), other DPPIV inhibitors, alpha2antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues(e.g., exendin-4) or amylin. Also, combinations with SGLT2 inhibitorssuch as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosinephosphatase 1, substances which influence deregulated glucose productionin the liver, such as, e.g., inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase, lipid loweringagents, such as HMG-CoA-reductase inhibitors (e.g., simvastatin,atorvastatin), fibrates (e.g., bezafibrate, fenofibrate), nicotinic acidand its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACATinhibitors (e.g., avasimibe) or cholesterol absorption inhibitors suchas for example ezetimibe, bile acid-binding substances such as forexample cholestyramine, inhibitors of ileac bile acid transport,HDL-raising compounds such as for example inhibitors of CETP orregulators of ABC1 or active substances for the treatment of obesity,such as, e.g., sibutramine or tetrahydrolipostatin, dexfenfluramine,axokine, antagonists of the cannabinoid 1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists orβ₃-agonists such as SB-418790 or AD-9677 as well as agonists of the5HT2c receptor.

It is also possible to combine the compounds with drugs for treatinghigh blood pressure such as, e.g., All antagonists or ACE inhibitors,diuretics, β-blockers, Ca-antagonists, etc., or combinations thereof.

The dosage required to expediently achieve such an effect is, byintravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day.For this purpose, the compounds of formula I prepared according to theinvention, optionally combined with other active substances, may beincorporated together with one or more inert conventional carriersand/or diluents, e.g., with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, or suppositories.

The Examples that follow are intended to illustrate the invention:

Preparation of the Starting Compounds:

EXAMPLE I Dimethyl2-bromo-1-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate

A solution of 15.0 g dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 5.15ml 1-bromo-2-butyne and 50 ml N,N-diisopropylethylamine in 280 ml oftetrahydrofuran is refluxed for one hour. The mixture is concentrated byevaporation, the residue is combined with approx. 100 ml of water andextracted three times with 70 ml of ethyl acetate. The extracts arewashed with 50 ml of water, dried and evaporated down. The crude productthus obtained is purified by column chromatography through silica gelwith methylene chloride/ethanol (1:0->49:1) as eluant.

Yield: 13.50 g (75% of theory)

R_(f) value: 0.82 (silica gel, methylene chloride/ethanol=9:1)

Mass spectrum (ESI⁺): m/z=315/317 (Br) [M+H]⁺

EXAMPLE II Methyl2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazol-4-carboxylate

43 ml of a 1 M solution of diisobutylaluminium hydride intetrahydrofuran are added dropwise within 20 minutes to a solution of13.5 g of dimethyl2-bromo-1-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in 220 ml oftetrahydrofuran under an argon atmosphere at −70° C. The mixture isstirred for a further four hours at −70° C., then 20 ml of a mixture of1 M hydrochloric acid and tetrahydrofuran are added dropwise. Afterheating to ambient temperature approx. 200 ml of water are added and themixture is extracted three times with 70 ml of ethyl acetate. Thecombined extracts are dried and evaporated down. The crude product thusobtained is purified by column chromatography through silica gel withpetroleum ether/ethyl acetate (4:1->1:1) as eluant.

Yield: 6.40 g (52% of theory)

Mass spectrum (ESI⁺): m/z=285/287 (Br) [M+H]⁺

EXAMPLE III2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

0.31 ml hydrazine hydrate, dissolved in 1 ml of ethanol, are addeddropwise at ambient temperature to a solution of 1.80 g methyl2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 25 ml ofethanol. Five minutes later 1.5 ml concentrated acetic acid are added,and the mixture is refluxed for 30 minutes. After cooling the solidprecipitate is suction filtered, washed with 10 ml of ethanol and 20 mldiethyl ether and dried.

Yield: 1.25 g (74% of theory)

Mass spectrum (ESI⁺): m/z=267/269 (Br) [M+H]⁺

EXAMPLE IV2-bromo-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

A mixture of 365 mg2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 265mg 2-chloromethyl-4-methyl-quinazoline and 210 mg potassium carbonate in6 ml acetonitrile is stirred for 17 h at ambient temperature. Then thereaction mixture is filtered through 5 g aluminium oxide with ethylacetate and the filtrate is evaporated down. The residue is trituratedin diisopropylether, separated from the ether and dried.

Yield: 300 mg (53% of theory)

Mass spectrum (ESI⁺): m/z=423/425 (Br) [M+H]⁺

The following compounds are obtained analogously to Example IV:

-   (1)    2-bromo-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=422/424 (Br) [M+H]⁺

-   (2)    2-bromo-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=382/384 (Br) [M+H]⁺

-   (3)    2-bromo-3-(2-butyn-1-yl)-5-(4-cyano-isoquinolin-3-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=463/465 (Br) [M+H]⁺

EXAMPLE V(S)-2-[(2-aminopropyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

A mixture of 0.36 g2-bromo-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,0.42 g (S)-1,2-diaminopropane dihydrochloride and 0.52 g potassiumcarbonate in 6 ml N-methylpyrrolidone is stirred for 2.5 h at 120° C.Then saturated aqueous sodium chloride solution is added and theprecipitate formed is separated off. The aqueous phase is extracted withethyl acetate, the combined organic phases are dried over sodiumsulphate and evaporated down.

Yield: 580 mg (approx. 60% pure)

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/ammoniumhydroxide=90:10:0.1)

The following compound is obtained analogously to Example V:

-   (1)    2-[(2-amino-2-methyl-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

R_(f) value: 0.25 (silica gel, methylene chloride/methanol/ammoniumhydroxide=90:10:0.1)

-   (2)    (S)-2-[(2-benzyloxycarbonylamino-prop-1-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Product (2) was obtained by reacting2-bromo-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-onewith (S)—N-(2-benzyloxycarbonylamino-prop-1-yl)-N-methyl-amine.

Mass spectrum (ESI⁺): m/z=565 [M+H]⁺

-   (3)    (S)-2-[(2-aminopropyl)amino]-3-(2-butyn-1-yl)-5-(4-cyano-isoquinolin-3-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/ammoniumhydroxide=90:10:0.1)

EXAMPLE VI(S)-2-[(2-tert-butyloxycarbonylamino-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

0.73 g di-tert. butyl pyrocarbonate are added at ambient temperature toa solution of 1.04 g(S)-2-[(2-aminopropyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-oneand 0.54 ml triethylamine in 200 ml dichloromethane. The solution isstirred for 16 h at ambient temperature and then evaporated down. Theresidue is taken up in ethyl acetate and in each case washed once withwater, dilute citric acid, water and saturated aqueous sodium chloridesolution. Then the organic phase is dried over sodium sulphate andevaporated down. The residue is purified by chromatography throughsilica gel (petroleum ether/ethyl acetate 1:1).

Yield: 0.40 g (30% of theory)

Mass spectrum (ESI⁺): m/z=476 [M+H]⁺

The following compound is obtained analogously to Example VI:

-   (1)    2-[(2-tert-butyloxycarbonylamino-2-methyl-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=490 [M+H]⁺

-   (2)    (S)-2-[(2-tert-butyloxycarbonylamino-propyl)amino]-3-(2-butyn-1-yl)-5-(4-cyanoisoquinolin-3-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=557 [M+H]⁺

EXAMPLE VII(S)-2-[N-(2-tert-butyloxycarbonylamino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

0.96 g potassium-tert-butoxide are added to an ice-cooled solution of0.39 g(S)-2-[(2-tert-butyloxycarbonylamino-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-onein 5 ml dimethylsulphoxide. The mixture is stirred at ambienttemperature, until the solution is clear. Then 53 μl methyl iodide areadded, and the solution is stirred for a further 3.5 h at ambienttemperature. Then water is added to the reaction solution, theprecipitate formed is separated off and washed with water. The driedprecipitate is purified by chromatography through silica gel (petroleumether/ethyl acetate 1:1).

Yield: 0.26 g (66% of theory)

Mass spectrum (ESI⁺): m/z=490 [M+H]⁺

The following compound is obtained analogously to Example VII:

-   (1)    2-[N-(2-tert-butyloxycarbonylamino-2-methyl-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=504 [M+H]⁺

-   (2)    (S)-2-[N-(2-tert-butyloxycarbonylamino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(4-cyano-isoquinolin-3-yl    methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=571 [M+H]⁺

EXAMPLE VIII Methyl2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylate

Under an argon atmosphere 38 ml of a 0.5 M solution ofpotassium-bis(trimethylsilyl)amide in toluene are added dropwise to anice-cooled solution of 6.64 g methoxymethyltriphenyl phosphoniumchloride in 140 ml of tetrahydrofuran over 10 min. The reaction mixtureis stirred for a further 15 min in the ice bath and then cooled to −70°C. Then a solution of 4.41 g methyl2-bromo-3-(2-butyn-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 40 ml oftetrahydrofuran is added dropwise over 30 min. After a further 45 minstirring at −70° C. the solution is heated to ambient temperature andstirred for another 1 h at this temperature. Then water is added to thereaction solution and this is extracted with ethyl acetate. The organicextracts are dried over sodium sulphate, the solvent is removed and theresidue is chromatographed through silica gel (cyclohexane/ethyl acetate9:1->7:3).

Yield: 2.67 g (55% of theory), pure trans compound

Mass spectrum (ESI⁺): m/z=313/315 (Br) [M+H]⁺

EXAMPLE IX 2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylicacid

A solution of 2.20 g lithium hydroxide in 175 ml of water is added to asolution of 3.50 g methyl2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylate in 140 mlof tetrahydrofuran. The solution is stirred for 4 h at ambienttemperature. Then 92 ml aqueous 1 M hydrochloric acid are added, and thesolution is cooled in the ice bath. The precipitate is separated off,washed with water and dried.

Yield: 3.30 g (99% of theory)

Mass spectrum (ESI⁺): m/z=299/301 (Br) [M+H]⁺

EXAMPLE X2-bromo-3-(2-butyn-1-yl)-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylicacid-(3-methyl-isoquinolin-1-ylmethyl)-amide

A solution of 3.50 g2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylic acid and1.30 g TBTU in 1.20 ml triethylamine and 30 ml of dimethylformamide isstirred for 15 min at ambient temperature. Then 1.09 g3-methyl-isoquinolin-1-ylmethylamine are added, and the resultingsuspension is stirred for 4 h at ambient temperature. Then ice-cooledwater is added and the precipitate is separated off. The precipitate isdissolved in dichloromethane, the solution is dried over sodium sulphateand the solvent is removed.

Yield: 1.38 g (78% of theory)

Mass spectrum (ESI⁺): m/z=453/455 (Br) [M+H]⁺

EXAMPLE XI2-bromo-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-onein a 1:1-mixture with2-chloro-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one

0.74 g2-bromo-3-(2-butyn-1-yl)-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylicacid-(3-methyl-isoquinolin-1-ylmethyl)-amide are stirred in 35 mlaqueous 4 M hydrochloric acid for 3 h at 85° C. After cooling to ambienttemperature dichloromethane is added and the solution is made alkalinewith sodium hydroxide solution. The organic phase is separated off andthe aqueous phase is extracted twice with dichloromethane. The combinedorganic phases are dried over sodium sulphate, the solvent is removedand the residue is purified through silica gel (dichloromethane/methanol99:1->95:5).

Yield: 0.39 g (1:1 mixture of the two title compounds)

Mass spectrum (ESI⁺): m/z=421/423 (Br) [M+H]^(+ and m/z=)377/379 (Cl)[M+H]⁺

Preparation of the End Compounds:

EXAMPLE 12-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

A mixture of 300 mg2-bromo-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,400 mg N-methyl-ethylenediamine and 210 mg potassium carbonate in 6 mldimethylsulphoxide is stirred for 8 h at 60° C. Then saturated aqueoussodium chloride solution is added and the aqueous phase is extractedwith ethyl acetate. The combined organic phases are dried over sodiumsulphate and evaporated down. The crude product is purified bychromatography through a silica gel column with methylenechloride/methanol (3:2) as eluant.

Yield: 85 mg (29% of theory)

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

The following compound is obtained analogously to Example 1:

-   (1)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=416 [M+H]⁺

-   (2)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one

Product (2) was obtained by reacting a 1:1 mixture of2-bromo-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-oneand2-chloro-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-onewith N-methyl-ethylenediamine according to the instructions describedabove. Mass spectrum (ESI⁺): m/z=415 [M+H]⁺

EXAMPLE 2(S)-2-[N-(2-amino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

1.4 ml trifluoroacetic acid are added dropwise to a solution of 250 mg(S)-2-[N-(2-tert-butyloxycarbonylamino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-onein 5 ml dichloromethane. The solution is stirred for 4 h at ambienttemperature, then diluted with dichloromethane and made alkaline withsaturated aqueous sodium carbonate solution. The organic phase isseparated off, washed with water, dried over magnesium sulphate andevaporated down. The residue is stirred with tert-butylmethylether andafter separation of the ether dried in vacuo at 40-50° C.

Yield: 161 mg (81% of theory)

Mass spectrum (ESI⁺): m/z=390 [M+H]⁺

The following compound is obtained analogously to Example 2:

-   (1)    2-[N-(2-amino-2-methyl-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenyl-methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=404 [M+H]⁺

-   (2)    (S)-2-[N-(2-amino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(4-cyano-isoquinolin-3-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

Mass spectrum (ESI⁺): m/z=441 [M+H]⁺

EXAMPLE 3(S)-2-[N-(2-aminopropyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

40 μl iodotrimethylsilane are added to a solution of 130 mg(S)-2-[(2-benzyloxycarbonylamino-prop-1-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-onein 3 ml dichloromethane. After stirring at ambient temperature for 1 and3 h, a further 100 μl of iodotrimethylsilane are added on each occasion.The solution is stirred for a further 4 h at ambient temperature andthen combined with 5 ml of methanol and evaporated down. Then 1 Mhydrochloric acid is added and the aqueous phase is washed twice withdichloromethane. The aqueous phase is made alkaline with sodiumcarbonate and extracted three times with dichloromethane. The organicextracts are dried over sodium sulphate, the solvent is removed and theresidue is purified through silica gel (dichloromethane/methanol1:0->3:1).

Yield: 30 mg (30% of theory)

Mass spectrum (ESI⁺): m/z=431 [M+H]⁺

The following compounds may also be obtained analogously to theforegoing Examples and other methods known from the literature:

-   (1)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-cyano-naphth-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (2)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyano-phenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (3)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(quinoxalin-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (4)    2-[N-(2-aminocyclopropyl)amino]-3-(2-butyn-1-yl)-5-(2-cyano-phenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (5)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-cyano-naphth-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (6)    2-[N-(2-amino-2-methyl-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (7)    2-[N-(2-amino-2-methyl-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(phenylcarbonyl    methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (8)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[3-(2-nitrophenyl)prop-2-en-1-yl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (9)    2-[N-(1-aminocycloprop-1-ylmethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (10)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-chloro-2-cyano-phenyl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (11)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-([1,5]naphthyridin-2-yl    methyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (12)    2-[N-(2-aminoprop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(quinoxalin-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (13)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(quinazolin-7-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (14)    2-[N-(2-aminoprop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(1-cyano-isoquinolin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (15)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-morpholin-4-ylquinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (16)    2-[N-(2-aminoprop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-phenyl-pyrimidin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (17)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2,3-dimethyl-quinoxalin-6-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (18)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(1-cyano-isoquinolin-3-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (19)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methoxy-phenyl)carbonylmethyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (20)    2-[N-(2-aminoprop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(2-methoxy-phenyl)-carbonylmethyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (21)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-buten-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (22)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(3-methyl-but-2-en-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (23)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(1-cyclopenten-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (24)    2-[N-(2-amino-2-methyl-prop-1-yl)-N-methyl-amino]-3-(1-buten-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (25)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-[(2-chloro-phenyl)methyl]-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (26)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-[(2-bromo-phenyl)methyl]-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (27)    2-[N-(2-amino-2-methyl-prop-1-yl)-N-methyl-amino]-3-[(2-iodo-phenyl)methyl]-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (28)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-[(2-cyano-phenyl)methyl]-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (29)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(furan-2-ylmethyl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (30)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(thien-3-ylmethyl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (31)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methoxy-naphth-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (32)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[3-(pentafluorophenyl)prop-2-en-1-yl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (33)    2-[(azetidin-3-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (34)    2-[N-(azetidin-3-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (35) 2-[N-(2-amino-1,1,2-trimethyl    prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (36)    2-[(3-methyl-azetidin-3-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)-methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (37)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (38)    2-[N-(2-amino-1-methyl-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (39)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-cyano-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one-   (40)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-cyano-pyridin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one-   (41)    2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one-   (42)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-one-   (43)    2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-([1,5]naphthyridin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one

(44)2-[N-(2-amino-prop-1-yl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(4,6-dimethylpyrimi-din-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-oneEx. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

EXAMPLE A

Coated tablets containing 75 mg of active substance 1 tablet corecontains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0mg magnesium stearate 1.5 mg 230.0 mgPreparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks about 13 mm in diameterare produced in a tablet-making machine and these are then rubbedthrough a screen with a mesh size of 1.5 mm using a suitable machine andmixed with the rest of the magnesium stearate. This granulate iscompressed in a tablet-making machine to form tablets of the desiredshape.

-   -   weight of core: 230 mg    -   die: 9 mm, convex 51 of 70

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

EXAMPLE B

Tablets containing 100 mg of active substance Composition: 1 tabletcontains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mgMethod of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

EXAMPLE C

Tablets containing 150 mg of active substance Composition: 1 tabletcontains: active substance 150.0 mg powdered lactose 89.0 mg corn starch40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesiumstearate 1.0 mg 300.0 mgPreparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm.

The granules, dried at 45° C., are passed through the same screen againand mixed with the specified amount of magnesium stearate. Tablets arepressed from the mixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

EXAMPLE D

Hard gelatine capsules containing 150 mg of active substance 1 capsulecontains: active substance 150.0 mg corn starch (dried) approx. 180.0 mglactose (powdered) approx.  87.0 mg magnesium stearate  3.0 mg approx.420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

EXAMPLE E

Suppositories containing 150 mg of active substance 1 suppositorycontains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mgPreparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE F

Suspension containing 50 mg of active substance 100 ml of suspensioncontain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 gmethyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 gdist. water ad 100 mlPreparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.

EXAMPLE G

Ampoules containing 10 mg active substance Composition: active substance10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

EXAMPLE H

Ampoules containing 50 mg of active substance Composition: activesubstance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilled waterad 10.0 mlPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

1. Compounds of formula I

wherein R¹ denotes an arylmethyl or arylethyl group, a heteroarylmethylor heteroarylethyl group, an arylcarbonylmethyl group, aheteroarylcarbonylmethyl group or an arylprop-2-enyl orheteroarylprop-2-enyl group, wherein the propenyl chain may besubstituted by 1 to 4 fluorine atoms or a cyano, C₁₋₃-alkyloxy-carbonylor nitro group, X denotes a C—R⁵ group, while R⁵ denotes a hydrogen atomor a C₁₋₃-alkyl group, R² denotes a hydrogen atom, a C₁₋₆-alkyl group,an aryl or heteroaryl group, a C₁₋₆-alkyl group substituted by a groupR_(a), where R_(a) denotes a C₃₋₇-cycloalkyl group wherein one or twomethylene groups may each be replaced independently of one another by anoxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)- group or by acarbonyl, sulphinyl or sulphonyl group, or a trifluoromethyl, aryl,heteroaryl, cyano, carboxy, C₁₋₃-alkoxy-carbonyl, amino-carbonyl,C₁₋₃-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,piperazin-1-ylcarbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl,arylcarbonyl, heteroarylcarbonyl, C₁₋₃-alkylsulphinyl,C₁₋₃-alkylsulphonyl, hydroxy, C₁₋₃-alkoxy, C₁₋₃-alkylsulphanyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, piperazin-1-yl or 4-(C₁₋₃-alkyl)-piperazin-1-yl group, atrifluoromethyl, carboxy, C₁₋₄-alkoxy-carbonyl, aminocarbonyl,C₁₋₃-alkylamino-carbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,piperazin-1-ylcarbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl,arylcarbonyl, heteroarylcarbonyl, C₁₋₃-alkylsulphinyl,C₁₋₃-alkylsulphonyl, C₁₋₄-alkoxy, C₁₋₄-alkylsulphanyl, amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or4-(C₁₋₃-alkyl)-piperazin-1-yl group, a C₃₋₇-cycloalkyl group wherein oneor two methylene groups independently of one another may each bereplaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group, or by a carbonyl, sulphinyl or sulphonyl group, or a C₃₋₆-alkenylor C₃₋₆-alkynyl group, R³ denotes a C₅₋₇-cycloalkenylmethyl groupoptionally substituted by a C₁₋₃-alkyl group, an arylmethyl orheteroarylmethyl group, a straight-chain or branched C₂₋₈-alkenyl groupwhich may be substituted by 1 to 15 fluorine atoms or a cyano, nitro orC₁₋₃-alkoxy-carbonyl group, or a straight-chain or branched C₃₋₈-alkynylgroup which may be substituted by 1 to 9 fluorine atoms or a cyano,nitro or C₁₋₃-alkoxy-carbonyl group, and R⁴ denotes an amino groupsubstituted by the groups R¹⁵ and R¹⁶ wherein R¹⁵ denotes a hydrogenatom, a C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl, aryl oraryl-C₁₋₃-alkyl group and R¹⁶ denotes a R¹⁷—C₂₋₃-alkyl group, while theC₂₋₃-alkyl moiety is straight-chain and may be substituted by 1 to 4C₁₋₃-alkyl groups, which may be identical or different, and theC₂₋₃-alkyl group may be linked to R¹⁷ from position 2 onwards, and R¹⁷denotes an amino or C₁₋₃-alkylamino group, an amino group substituted bythe groups R¹⁵ and R¹⁸ wherein R¹⁵ is as hereinbefore defined and R¹⁸denotes a C₃₋₁₀-cycloalkyl-C₁₋₂-alkyl- group substituted in the 1position of the cycloalkyl group by R¹⁹ or a C₃₋₁₀-cycloalkyl groupsubstituted in 1 or 2 position by a R¹⁹—C₁₋₂-alkyl- group, while R¹⁹denotes an amino or C₁₋₃-alkylamino group, an amino group substituted bythe groups R¹⁵ and R²⁰ wherein R¹⁵ is as hereinbefore defined and R²⁰denotes a C₄— or C₈₋₁₀-cycloalkyl group wherein a methylene group fromposition 3 onwards of the C₄— or C₈₋₁₀-cycloalkyl group is replaced byan —NH— group, or an amino group substituted by the groups R¹⁵ and R²¹wherein R¹⁵ is as hereinbefore defined and R²¹ denotes a C₃₋₄— orC₈₋₁₀-cycloalkyl group substituted in the 2 or 3 position by an amino orC₁₋₃-alkylamino group, while the above-mentioned groups R¹⁸, R²⁰ and R²¹may be mono- or disubstituted by R_(b), the substituents may beidentical or different and R_(b) denotes a fluorine atom, a C₁₋₃-alkyl,trifluoromethyl, cyano, amino, C₁₋₃-alkylamino, hydroxy or C₁₋₃-alkyloxygroup, and wherein one or two methylene groups of the cycloalkyl groupindependently of one another may each be replaced by an oxygen orsulphur atom or by an —NH— or —N(C₁₋₃-alkyl)- group, or by a carbonyl,sulphinyl or sulphonyl group, while by the aryl groups mentioned in thedefinition of the above groups are meant phenyl or naphthyl groups,which may be mono-, di- or trisubstituted independently of one anotherby R_(h), while the substituents may be identical or different and R_(h)denotes a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl,cyano, nitro, amino, aminocarbonyl, C₁₋₃-alkoxy-carbonyl,aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino,C₁₋₃-alkyl, cyclopropyl, ethenyl, ethynyl, morpholinyl, hydroxy,C₁₋₃-alkyloxy, difluoromethoxy or trifluoromethoxy group, and whereinadditionally each hydrogen atom may be replaced by a fluorine atom, bythe heteroaryl groups mentioned in the definition of the above-mentionedgroups is meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl,benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, or ismeant a pyrrolyl, furanyl, thienyl or pyridyl group, wherein one or twomethyne groups are replaced by nitrogen atoms, or is meant an indolyl,benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group,wherein one to three methyne groups are replaced by nitrogen atoms, andthe above-mentioned heteroaryl groups may be mono- or disubstituted byR_(h), while the substituents may be identical or different and R_(h) isas hereinbefore defined, by the above-mentioned cycloalkyl groups asdefined are meant both monocyclic and also polycyclic ring systems,while the polycyclic groups may be annelated, spiro-linked or bridged instructure, while, unless otherwise stated, the above-mentioned alkyl,alkenyl and alkynyl groups may be straight-chain or branched, while thecarboxy groups mentioned in the definition of the above-mentioned groupsmay be replaced by a group which may be converted in vivo into a carboxygroup or by a group which is negatively charged under physiologicalconditions, and the amino and imino groups mentioned in the definitionof the above-mentioned groups may be substituted by a group which can becleaved in vivo, the tautomers, enantiomers, diastereomers, the mixturesthereof, the prodrugs thereof and the salts thereof.
 2. Compounds offormula I according to claim 1, wherein R¹ and R⁴ are defined asmentioned in claim 1, X denotes a —CH group, R² denotes a hydrogen atom,a C₁₋₄-alkyl, C₃₋₆-cycloalkyl or phenyl group and R³ denotes a1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enyl-methyl,furanyl-methyl, thienylmethyl, chlorobenzyl, bromobenzyl, iodobenzyl,methoxybenzyl or cyanobenzyl group, the enantiomers, the diastereomers,the mixtures thereof and the salts thereof.
 3. Compounds of formula Iaccording to claim 2, wherein R¹ denotes a phenylmethyl,phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl,pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl,isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl,naphthyridinylmethyl or benzotriazolylmethyl group which may besubstituted in each case by one or two fluorine, chlorine, bromine atomsor one or two cyano, nitro, amino, C₁₋₃-alkyl, C₁₋₃-alkyloxy andmorpholinyl groups, while the substituents are identical or different,R² denotes a hydrogen atom, R³ denotes a 1-buten-1-yl, 2-buten-1-yl,2-butyn-1-yl, cyclopent-1-enyl-methyl, furanyl-methyl, thienylmethyl,chlorobenzyl, bromobenzyl, iodobenzyl or cyanobenzyl group and R⁴denotes an N-(2-aminoethyl)-N-methyl-amino group wherein the ethyl groupmay be substituted by 1 to 4 methyl groups, the tautomers, the mixturesthereof and the salts thereof.
 4. Compounds of formula I according toclaim 3, wherein R¹ denotes a isoquinolinylmethyl, quinazolinylmethyl orbenzyl group which may be substituted by a methyl or cyano group, R²denotes a hydrogen atom, R³ denotes a 2-butyn-1-yl group and R³ denotesan N-(2-aminoethyl)-N-methyl-amino, N-(2-aminopropyl)-N-methyl-amino orN-(2-amino-2-methylpropyl)-N-methyl-amino group, the tautomers and thesalts thereof.
 5. The following compounds of formula I according toclaim 1:2-[N-(2-aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(3-methyl-isoquinolin-1-yl)methyl]-3,5-dihydro-imidazo[4,5-c]pyridin-4-oneas well as the tautomers and the salts thereof.
 6. A pharmaceuticalcomposition comprising the compound according to claim 1 or aphysiologically acceptable salt thereof together with one or more inertcarriers and/or diluents.
 7. Process for preparing the compounds offormula I according to claim 1, the process comprising a) providing acompound of general formula II

wherein R¹ to R³ and X are defined as mentioned in claim 1 and Z¹denotes a leaving group such as a halogen atom, a substituted hydroxy,mercapto, sulphinyl, sulphonyl or sulphonyloxy group, and b) reactingthe compound of formula II with R⁴—H or salts thereof, where R⁴ isdefined as in claim
 1. 8. Process for preparing the compounds of generalformula I according to claim 1, the process comprising a) deprotecting acompound of general formula III

wherein R¹, R², R³ and X are defined as mentioned in claim 1 and Z²denotes one of the groups mentioned for R⁴ in claim 1 that contains anamino group not directly linked to the basic imidazopyridinone structureand wherein said amino group not directly linked to the basicimidazopyridinone structure is protected by a tert.-butyloxycarbonylgroup.